Biotech / Biomedical

Most virus tests look for telltale DNA sequences or other markers that signal the presence of a particular pathogen. However, Dr. Adrian di Biscelia's laboratory at the St. Louis University School of Medicine has developed a new open-ended approach that can signal the presence of any virus or other blood-borne pathogen. The technique not only identifies known viruses, but also finds whether there are previously uncharacterized pathogens.

The technique relies on whole-genome next generation DNA sequencing. Whole-genome sequencing refers to reading all the A, T, C, G nucleotides present in the total DNA of a person. With major advances in high throughput sequencing technology over the past several years, the cost and speed of whole genome sequencing has dropped precipitously--to the point that is now practical for individual patients to have their personal genomes sequenced in a matter of hours. The first human genome sequencing took 13 years to finish and was just completed in 2003.

With the complete human genome sequence available as a reference, identifying foreign DNA in human samples is really more of an information processing exercise than a biochemical analysis. Essentially, DNA extracted from a person's blood, for example, can be sequenced and then compared with a reference human genome sequence. If there are extra leftover DNA pieces after this comparison, they must be from some non-human organism in the blood.

If the additional DNA is from a known virus, it is easy to identify it. However, if the extra DNA does not match any known viruses, then it is something new. Comparison of the DNA with known viruses would likely provide valuable information, in most cases, to help classify even new viruses and provide clues as to their virulence. The technique could provide a new way to rapidly catch new emerging viruses, such as the Middle East Coronavirus (MERS) which surfaced about a year ago.

You can read more about this development in St Louis University's press release.

In a unanimous decision the Supreme Court ruled today that natural genes are not patentable. The ruling boils down to the observation that patents must cover new inventions, not simply discoveries of natural phenomena. As stated in the Court's opinion, "genes and the information they encode are not patent eligible...simply because they have been isolated from the surrounding genetic material."

The opinion, written by Clarence Thomas points out that, "The Patent Act permits patents to be issued to '[w]hoever invents or discovers any new and useful . . . composition of matter,'" but, "groundbreaking, innovative, or even brilliant discovery does not by itself satisfy" this criteria. "Myriad did not create or alter either the genetic information encoded in the BCRA1 and BCRA2 genes or the genetic structure of the DNA"

The Court did validate patent claims to synthetic versions of genes containing just the key parts that produce the protein--in other words cDNA (complementary or cloned DNA). With cDNA, fragments of a gene's DNA are pieced together with other pieces of DNA to produce an non-natural construction of a gene. The justices affirmed patent rights to cDNA based on the reasoning that, "the lab technician unquestionably creates something new when cDNA is made."  However, it is not clear from the ruling how broad cDNA claims could be. Can a company claim rights to any cDNA made to mimic a particular gene, or are its right limited to the particular cDNA made in their labs?

The Court also specifically pointed out that it has not ruled on genes in which the natural DNA sequence has been altered, innovative methods to isolate genes, and applications that utilize particular knowledge about natural gene sequences. These are all reasonable subjects for patents.

The ruling was not unexpected and will not likely have an immediate effect on the biotech industry or Myriad Genetics as discussed in more detail a related article The Significance of the Myriad Gene Patent Decision.  In fact, Myriad's press release emphasized the point that the Court upheld their claims to the synthetic cDNA version of the genes they constructed for their BRCA gene tests. However, the ruling does certainly clear the way for other laboratories to test for the presence of the BRCA gene mutations, especially if they use techniques such as DNA sequencing that do not require synthetic cDNA constructions as references.

While there may be some concern that the ruling may make companies and investors less likely to put resources into new genetic discoveries, it remains to be see if there will be any long term impact on biotech investment and innovation.  In fact, the case does clear up some longstanding murkiness about what aspects of genetic discoveries can actually be patented and owned by company. It seems likely that this increased clarity may enable some companies to more confidently invest in research projects without having to worry about unknown patent holders claiming rights to the genes they are working on.

You can find more background about the Myriad case in The Supreme Court Reviews Myriad's Gene Patents, and, for information about gene patents in general, check out Can a Company Really Own Your DNA?

Two days ago the Food and Drug Commissioner Margaret Hamburg authorized emergency use of the CDC's Novel Coronavirus 2012 Real-time RT-PCR Assay for the detection of the Middle East Coronavirus (MERS). Under the Pandemic and All-Hazards Preparedness Act which was enacted in 2006 reauthorized in March this year the FDA can allow limited use of a non-approved medical products to address public health emergencies. The FDA authorization grants public health laboratories in the US clearance to use the CDC's MERS detection kit to identify the virus in patient samples.

Last month a similar authorization was granted for a CDC assay to detect the H7N1 Bird Flu. Previous to these two approvals, the last medical devices authorized under the emergency act were for detection of the H1N1 Influenza strain in May of 2009.

On May 29, Health and Human Services Secretary Kathleen Sebelius declared MERS as a potential public health emergency. The authorization of the detection assay for this virus is intended to enable rapid identification and monitoring of the spread of the disease to minimize its potential impact. So far, no cases of MERS have been reported in the US. Worldwide 55 people have been reported to have come down with the virus and 31 of these died. It is the high mortality rate that has caused concern.

MERS is related to the Severe Acute Respiratory Virus (SARS) in that they are both coronaviruses. However, the two viruses are not of the same lineage. According to an announcement from the coronavirus study group, MERS is actually most closely related to bat coronaviruses. However, it does not appear that most of the affected individuals were exposed to the virus by contact with bats. Also, though, there does not appear to be evidence of "sustained community transmission" according to the report. For example, of the 55 cases reported so far, 40 were concentrated in Saudi Arabia.  There have only been isolated cases in the other seven countries where it has been reported.

As a result of the limited transmission, the study group believes that the MERS virus strain has jumped from bats to another animal. The thinking is that this other infected animal species is in closer contact with humans than bats, and that it is by interaction with this other viral-carrying animal that most humans become infected. However, the fear, of course, is that the virus might eventually adapt to enable efficient human-to-human transmission allowing it to spread much more rapidly.

You can find more information on MERS at the CDC website, and the About Senior Travel Guide offer a guide for overseas travel.

Researchers from the Nabel laboratory at the National Institute of Allergy and Infectious Diseases (NIAID) developed a synthetic nanoparticle flu vaccine that showed much higher effectiveness in both mice and ferrets compared with the standard seasonal vaccine. If the work pans out, it could enable production of a vaccine that provides better protection against more stains of influenza and is easier and faster to produce than the current seasonal vaccines.

The group produced a self-assembling nanoparticle that stimulated a much stronger immune response than the standard flu vaccine by using a fusion of the iron binding protein ferritin to influenza virus protein hemagluttinin (HA). The ferritin protein naturally assembles to form a nanostructure that has 24 protrusions. The ferritin-HA hybrid was designed so that the HA molecules were exposed at the end of the protrusions, enabling the immune system to easily recognize and respond to the antigen. The structure produced an immune response about 10-fold stronger than the standard vaccine in ferrets, which is a common model animal for influenza studies.

Although the antigenic nanoparticle was built using the 1999 strain of H1N1 flu, the ferrets' immune response also protected them against other H1N1 strains with slightly different versions of the HA protein. For more universal flu protection, though, a vaccine would need to contain antigenic nanoparticles displaying HA molecules from other flu strains. There are 17 known HA subtypes.

This work exemplifies general efforts from a number of research groups to develop a more potent and universal vaccine to combat seasonal influenza. The effectiveness of the current seasonal flu vaccines vary significantly from year to year depending on a number of factors, including how well the CDC can guess which strains will likely be in wide circulation for the upcoming season. Also, current vaccines are poorly effective at immunizing the elderly, a segment of the population most at risk for serious health-related complications result from influenza.

Other efforts to improve flu vaccine performance include DNA-based vaccines, research on antibodies that recognize multiple flu strains, and BiondVax's Multimeric-001 which is currently in clinical trials.

You can find more information on the current study at the Nature News.

Last week researchers at Oregon Health and Science announced they had made human embryo clones using skin cells. The technique was similar to the one used to clone Dolly, the sheep, almost 20 years ago. Why has it taken so long to clone humans? Are we that different than sheep?

In fact, cloning resarch has a long history and there has been pretty continuous progress with mammalian cloning over the past 25 years. Mice, dogs, cats, and even camels have been cloned. The latest result in Oregon is only the most recent discovery in a field that has been gradually unraveling the processes of how a single cell can develop into complex organism for over 100 years starting with work on sea urchins.

Of course, this recent work by the lab in Oregon has received much more attention than most other cloning experiments because it involves humans. The experiment sparked immediate controversy as soon as it was published. However, as a recent USA Today article points out, a clone is basically an identical twin so there is nothing particularly strange about them.

Also, the Oregon group did not actually create a human clone, just a cloned embryo. While the work has brought us close to being able to fully clone a human being, this is not really the main purpose of the study. Based on the group's previous work with primates, the embryo would not likely even be able to develop into a human. We still do not known enough about development to successfully produce a cloned person.

This gap in our understanding, though, is sort of the point. Although only time will tell if this technique will ever find useful clinical applications, the embryos produced by this process will be very useful to generate embryonic stem cells for biomedical research. The technique provides an essential research tool to investigate the process of development and differentiation that enables one cell to produce a whole person. It provides a basis on which to build a more sophisticated understanding of this miraculous transformation. In the end, it is this deeper knowledge that will provide new and better medical treatments.

You can read more information on this cloning breakthrough and the history of cloning research in two recently posted articles:

• Researchers Clone a Human Embryo, Finally!
• The History of Cloning Research

Back in February the Supreme Court heard arguments from farmer Vernon Bowman on why he didn't need to pay royalties to Monsanto for growing their patented GMO soybeans that have been genetically modified to be resistant to the pesticide in Round-Up. Today, Mr. Bowman lost his case when the Court unanimously ruled against him.  He owes Monsanto $84,000 in royalties.

Bowman bought uncharacterized soybeans intended as animal feed from a local supplier. He admited that he thought most of the generic soybeans would probably be Round-Up ready GMO varieties even though they weren't labeled that way or sold as crop seeds. Since he didn't specifically buy Round-Up ready seeds, however, he argued that he didn't infringe on Monsanto's patent. In fact, he claimed it was the seeds themselves that replicated the patented invention.

All the Justices disagreed with Bowman. "But we think that blame-the-bean defense tough to credit." noted Justice Elena Kagen in delivering the Court's opinion. "Bowman was not a passive observer of his soybeans' multiplication; or put another way, the seeds he purchased...did not spontaneously create eight successive soybean crops....Bowman devised and executed a novel way to harvest crops from Roundup Ready seeds without paying the usual premium."

Justice Kagen points out that the Court's opinion is based understanding that, "Under the doctrine of patent exhaustion, the authorized sale of a patented article gives the purchaser, or any subsequent owner, a right to use or resell that article. Such a sale, however, does not allow the purchaser to make new copies of the patented invention."

For more on the ruling, see a summary on ScienceInsider.

The lab of Rudolf Jaenisch, who developed the first transgenic mouse in 1974, has developed a new approach to genetically engineer mice in just weeks, rather than years which are currently needed. This new technique does not rely on engineering embryonic stem (ES) cells, but rather, directly introduces the genetic changes in developing mouse embryos. In addition to making production of transgenic mice and rats for laboratory research faster and easier, it should also work with other types of organisms whose embryonic cells are difficult to engineer and manipulate.

The new approach takes advantage of a unique response bacterial developed as a defense against invading viruses. Bacteria can target and cut the DNA of invading viruses. To do this, they use short sequences of DNA that match some part of the DNA of the invading virus. Many bacteria seem to have a "catalog" of short stretches of DNA that match parts of many different types of viruses. These regions of DNA were dubbed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) when they were first discovered.

Researchers found that they could co-opt this bacterial defense system to target and inactivate specific genes in more advanced non-bacterial cells. To do this, they only needed to introduce the gene that cuts the targeted viral DNA in bacteria--the CRISPR-associated protease (Cas). Basically, it seems that almost any gene in most cells can be cut by introducing DNA that makes the Cas protein and a CRISPR construct with a short sequence that recognize some small part the gene. Even though a cell will fix a gene that has been cut, it does not get fixed correctly (because of the way Cas cuts it).  Then, the gene will no longer work, so it has been "knocked out".

Inactivating or "knocking out" genes is a common approach researchers use to understand how particular genes function and also generate mice or rat strains that model various human diseases. One of the big difficulties of engineering animals with certain genes knocked out, though, is that almost all genes come in pairs--one from each parent. Both copies of a gene need to be inactivated to fully knockout a gene. Unless the knock out technique is very efficient, this is rare. However, the CRISPR approach seems to be exceptionally effective.

In a Cell publication this week, the researchers in Dr. Jaenisch's lab describe how they were able to simultaneously and specifically knock out two genes with a single injection of a mouse embryo. Further, they also used the technique to produce embryonic mouse stem cells with disruptions of 5 distinct genes simultaneously. Mice produced using these embryonic stem cells would then carry all 5 of these mutations.

For a more information, you can read the press release from the Whitehead Institute at MIT describing the paper.

Thirteen of the world's leading stem cell researchers just published a statement in the European Molecular Biology Organization (EMBO) Journal expressing alarm about initiatives to deregulate stem cell therapies. Recent actions by the Italian government allowing unapproved stem cell treatments precipitated the researchers' statement.

Last year, the Italian Medicines Agency or AIFA (equivalent to the FDA in the US), ordered a halt to unapproved stem cell treatment program being carried out at the Brescia Civilian Hospital on the basis that there was no scientific evidence for its effectiveness. The treatment was being done under the direction of the Stamina Foundation, founded by Davide Vannoni, a psychology professor at the University of Udine. According to an article in Nature, 32 terminally ill patients, mostly children, were being treated using the therapy. However, the treatment was never approved by AIFA.

Protests in response to the interruption of the treatment prompted Italy's Minister of Health, Renaldo Balduzzo to override the AIFA order in March. Despite the strong objections in an open letter to the Minister from thirteen Italian scientists researching stem cells, the Italian Parliament, in one of its last acts before new elections, issued a decree allowing the Stamina therapy to continue.

As a result, the authors of the EMBO article felt the need to emphasize the importance of "strident regulation" of medical applications of stem cells to ensure "the translation of science into effective therapies." They point to the current situation in Italy, as well as recent stem cell regulatory battles in the US and a case in Germany in which unregulated stem cell treatments resulted in death, as examples of how rules set out by regulatory bodies such as the FDA and EMA have so far been effective in protecting patients from serious risks associated the indiscriminate use of unproven therapies, and voice their concern that these rule seem to be changing for stem cell therapies.

In reference to the current case in Italy, the article notes that, "The treatment, offered by a private non-medical organization, may not be safe, lacks a rationale, and violates current national laws and European regulation." Also, the authors understand the augment for reinstating treatment in the Italian case was that "safety is not a concern in the face of severely ill children or adults, for whom there are no therapeutic alternatives." However, they emphasize that:

"Compassion only applies when one offers a safe and potentially effective remedy. That a remedy is effective must be supported by published clinical data. If such data are not available, there is no legitimate assumption of effectiveness in the individual patient, and therefore no 'compassion'."

You can read more about the article in the press release from EMBO.

Much has been made of the importance of the lawsuit brought by the Association of Molecular Pathology and the ACLU against Myriad Genetics over the BRCA patents. The case was just heard by the Supreme Court and some feel a decision in favor of Myriad's patents would stifle research and enable companies to own our genes, whereas others voice concern that a decision against Myriad would undermine the biotech industry and stop the flow of innovative new medical technology. In fact, both positions seem a bit overblown.

Although the case has important legal implications, the Court's ruling is unlikely to cause a sea change in the biotech industry or biomedical research. Myriad Genetics is a 20 year old biotech company with over $500 million in annual revenue and a strong technology base, and investigators have been busily pursuing gene-related research since before Myriad was founded without running afoul of the tens of thousands of gene patents that have been granted since the mid-1980s. Large numbers of life science researchers at public and academic institutions regularly interact and collaborate closely with companies, and have done so for a few decades. The situation with Myriad is actually an outlier that seems to have arisen more from Myriad's business practices than from legal issues.

To get a sense of what prompted the lawsuit and what is really at stake in the Myriad Case, take a look at The Significance of the Myriad Gene Patent Decision.

Session on Obamacare's Impact on Biotech

I started off the conference on Wednesday attending a session discussing the Affordable Care Act. The new law brings up some concerns for biotech businesses since the act significantly affects which drugs are reimbursed under health insurance, particularly Medicare and Medicaid. Changes in how drugs are sold and paid for will influence how they are developed and produced. It was an illuminating discussion that I intend to provide further details on in an article later. However, the short version is that there has to be a return for the costly and risky investment required to develop new innovative drugs, otherwise these new treatments won't be developed.

Out with the Old Chair and In with the New

After the morning sessions, the Wednesday keynote session started off with 96-year old Dr. George Rosenkranz receiving the Biotechnology Heritage Award for his work leading to the development of oral contraception. Then, Dr. Thomas Watkins, the outgoing Chair of the board for BIO, spoke about the advocacy work the group has done to ensure passage of legislation to make the patent system more transparent, provide input to the first BioEconomy blueprint from the President, strengthen SBIR grant funding, and fight against legislation for GMO labeling and weakening fuel standards that would  have hurt biofuel development.

Dr. Walkins concluded his remarks by passing the stage to the new incoming BIO Chair, Dr. Rachel King, the CEO of GlycoMimetics. Dr. King emphasized that her goal in working with BIO is to "improve the climate for innovation" and outlined three priorities of focus to achieve this goal during her term as chair: (1) promoting communication about the importance of biotechnology, (2) ensuring a strong and flexible FDA approval process, and (3) protecting incentives for crucial innovation.

Keynote Presenation from Simpson-Bowles Deficit Reduction Plan

Following Dr. King, the main part of the session began when the Jim Greenfield, CEO of BIO, introduced Senator Alan Simpson and Erskine Bowles, former co-chairs of the President's Fiscal Commission which drafted a plan that has been largely ignored by both political parties to balance the US governmental budget. They have continued the work of the committee by forming the Moment of Truth Project, which just recently released an updated version of the plan.

In his introductory remarks, Jim Greenwood pointed out that the US debt has grown from $3 trillion to $12 trillion in the 20 years since the first BIO conference in 1993, and 20% of the annual deficit is Medicare, which is estimated to grow to a full third by the end of the decade. The overarching question of whether Congress and the President are even capable of passing the reform needed to fix this problem was the focus of the discussion that Jim Greenwood moderated with the two senators. I can hardly do justice to the the very entertaining and insightful hour of conversation the three of them had in a few lines, but the bottom line was that the solution requires some increase in tax revenue and relatively small changes in entitlements phased in over the new few decades.

The difficulty, of course, is getting the politicians, who are elected by districts overwhelming dominated by a single political party and lobbied by strong political groups representing defined constituencies, to act on the compromise proposal. In particular, Senator Simpson pointed out the unreasonableness of the AARP to accept even very modest adjustments in social security phased in over 50 years. To get a sense of his frustration, and the directness of the lively discussion, take a look at the letter he sent the California Association of Retired Americans last year. When asked about the harsh and pointed comments in the letter, he didn't back off a bit.

A Global Perspective on Biotechnology

The day ended with Scientific American's WorldView Global Biotechnology annual session that was moderated by CNN's Fareed Zakaria. After introductions, the discussion started with Dr. Zakaria and Trevor Muendel, CEO of the Bill and Melinda Gates Foundation, talking about how innovation is not necessarily a new chemical compound that effectively treats some incurable disease but is also new approaches to formulating or delivering medicine that are suitable to the real conditions in the developing world. As example, he mentioned things like vaccines stable at temperatures of 100 degrees and effective with a single dose, or how to make medicines affordable for these countries, such a new Meningitis vaccine the Foundation is distributing in N. Africa for just 52 cents a dose.

After this initial chat, the WorldView talk was broadened with additional panelists, such as Sam Pitroda, Advisor to the Prime Minister of India, and Dr. Robert Hariri, CEO of Celgene Cellular Therapeutics, a subsidiary of Celgene. The session covered a number of topics dealing with how the first-world advances in healthcare and biotechnology can be effectively applied in developing countries which don't have the infrastructure and resources available in the US and Europe.

Check Out EY's Report on the Biotech Industry

The conference continued on Thursday but I didn't attend the last day. I had a great time the three days I was able to be there, and learned many new things. In the coming days or weeks, I plan to add a few longer articles that cover some of this information in a bit more detail, such as the summary of the Ernst and Young Global Report on the Biotechnology Industry.