Prabowo Widodo
Reed Jobs, the visionary behind Yosemite, is making significant strides in the fight against cancer, carving out a distinct identity in the competitive landscape of venture capital. Known for his candid demeanor, self-deprecating humor, and a clear passion for his work, Jobs has strategically positioned Yosemite as a pivotal player in oncology-focused biotechnology. While acknowledging his famous lineage, Jobs prefers to spotlight the groundbreaking work of his firm, which launched in 2023 with a bold mission: to build biotech companies from the ground up, translating nascent academic research into clinical realities through a unique blend of philanthropy and traditional venture capital. Three years into its journey, Yosemite is not merely ambitious but is rapidly evolving, driven by the accelerating convergence of artificial intelligence (AI) with drug discovery and clinical trial design.
Yosemite’s Unique Model: A Hybrid Approach to Oncology Innovation
Yosemite’s operational model is a strategic departure from conventional venture capital. The firm’s singular focus on oncology, which represents approximately 40% of the entire biotech sector, allows for specialized expertise and targeted investment. Crucially, Yosemite doesn’t just invest in existing companies; it actively incubates and builds new biotech ventures from early-stage academic breakthroughs. This "company-building" philosophy is rooted in the belief that many cures for cancer are not simply waiting to be discovered in pharmaceutical pipelines but need to be meticulously crafted from novel scientific insights.
To de-risk these nascent ideas, often fragile in their university lab origins, Yosemite employs a hybrid funding mechanism. A significant portion of its capital, 2.5% of the fund’s assets under management, is allocated to a donor-advised fund, supplemented by an additional $1 million annually from its management fees. This non-dilutive, no-strings-attached philanthropic grant money acts as a critical catalyst, allowing foundational research to progress without the immediate pressure of commercial viability. This unique approach has already yielded tangible results, with two of the 20 companies in Yosemite’s inaugural fund directly emerging from these early grants, demonstrating the power of bridging the gap between academic innovation and commercial development.
Having recently announced the first close of its second fund, targeting $350 million, Yosemite is in a period of intense activity, expanding its team to 17 and onboarding new partners. Approximately one-third of this new capital is earmarked for companies Yosemite creates or co-builds with academic institutions like Yale, Berkeley, and Stanford. The remaining two-thirds are deployed into promising companies founded by others, reflecting a balanced strategy of organic creation and strategic investment. This dual approach underscores Yosemite’s commitment to not only identifying but also actively shaping the future of oncology.
A Biotech Landscape Transformed: From Post-Pandemic Chill to Acquisitive Spree
Yosemite’s journey began amidst a challenging period for the biotech sector. When Reed Jobs first discussed his vision at TechCrunch Disrupt nearly three years ago, the industry was grappling with the aftermath of a post-pandemic crash. The widely tracked XBI (SPDR S&P Biotech ETF) was significantly down from its 2021 highs, reflecting a broader investor conservatism and a slowdown in initial public offerings (IPOs). Valuations had retracted, and capital allocation became more cautious, particularly for early-stage, high-risk ventures characteristic of oncology.
However, the landscape has dramatically shifted in the intervening years. Several key factors have converged to revitalize the biotech market. A more favorable interest rate environment has eased capital costs, making long-term investments in R&D more attractive. More significantly, the pharmaceutical industry is on the precipice of its largest patent cliff in history, with blockbuster drugs generating hundreds of billions in revenue set to lose exclusivity in the coming years. Faced with this impending revenue gap and sitting on record cash reserves accumulated during the pandemic, major pharmaceutical companies have embarked on an aggressive acquisitive spree over the past eight to twelve months.
This renewed appetite for innovation has created unprecedented opportunities for biotech firms. High-profile exits underscore this trend, such as Eli Lilly’s acquisition of cancer drug developer Kelonia for an estimated $7 billion, and significant advancements in antibody-drug conjugates (ADCs). A standout example is Revolution Medicines, which has achieved remarkable success in targeting KRAS, a gene long considered "undruggable" and a major driver in pancreatic cancer. Their breakthrough has reportedly doubled the survival rate for the most common form of pancreatic cancer, extending it from 12 to 24 months—a monumental achievement that has materialized only within the last year, injecting palpable optimism into the field. This confluence of market dynamics and scientific breakthroughs has validated Yosemite’s early commitment to high-risk, high-reward oncology innovation.
The AI Revolution: Reshaping Drug Discovery and Clinical Trials
Artificial intelligence has rapidly transitioned from a speculative curiosity to a foundational pillar of Yosemite’s strategy. Reed Jobs emphasizes that AI is now a "huge part of what Yosemite does," recognizing its transformative potential across the healthcare spectrum.
The immediate impact of AI is evident in improving the efficiency of healthcare delivery, particularly in areas historically resistant to technological adoption. American hospitals, often characterized by outdated systems still relying on fax machines and even floppy disks, present fertile ground for AI integration. AI can revolutionize call centers, such as 911 triage, making 24/7 operations more cost-effective and efficient. Its applications extend to streamlining electronic health records (EHRs), enhancing radiology diagnostics, and automating pathology analysis, thereby freeing up human experts for more complex tasks.
However, Jobs’ keenest interest lies in AI’s application to clinical trials—the most significant cost and time sink in drug development. A typical Phase 3 cancer trial can cost approximately $260 million, with only about one in three succeeding. A major bottleneck is patient recruitment and retention. AI offers a revolutionary solution through the development of "synthetic control arms." By leveraging vast amounts of existing patient data, AI can construct a computer-generated stand-in for the untreated comparison group. This innovation means that instead of recruiting a full control group, researchers only need to enroll patients for the active treatment arm, effectively halving the required patient numbers and dramatically accelerating trial timelines. The U.S. Food and Drug Administration (FDA) is actively exploring and "leaning into" the adoption of such AI-driven methodologies, signaling a significant shift in regulatory acceptance.
In drug discovery, AI is proving to be a "fantastic advancement" for democratizing science and accelerating research. While AI may not always perform tasks "better" than human scientists, its unparalleled speed and ability to deliver reproducible outcomes for "grunt work" are invaluable. Historically, only about 15% of the human genome was considered "druggable" because the complex interactions between proteins made direct targeting exceptionally difficult. AI is rapidly changing this paradigm by identifying cryptic pockets and novel binding sites on previously intractable proteins. The example of KRAS, a protein long dubbed a "death star" due to its smooth, featureless surface, illustrates this perfectly. While scientists at Amgen initially discovered a "cryptic pocket" leading to the first KRAS inhibitor, Lumakras, AI has since expanded this discovery by identifying other targetable variants and devising creative new strategies to block its function, opening new avenues for treatment.
Tackling the "Undruggable": Yosemite’s Bold Portfolio
Yosemite’s investment strategy is characterized by a daring pursuit of historically "undruggable" targets, exemplified by its focus on some of the most formidable challenges in cancer biology.
The p53 Challenge: The firm’s most ambitious endeavor is tackling p53, often referred to as the "guardian of the genome." This tumor suppressor gene is critically important for preventing cancer, yet it is the most frequently suppressed gene across human cancers. Almost every cancer must disable p53 to establish itself. Jobs highlights that elephants, famously resistant to cancer, possess dozens of copies of p53, while humans have just one, making it vulnerable to mutation. Reactivating or attacking mutated forms of p53 represents one of cancer’s most sought-after "Achilles’ heels." Despite decades of research, this has never been achieved. Yosemite is pursuing this monumental challenge with three different portfolio companies, each employing distinct strategies, confident that they have identified a way to target an exposed marker across various p53 mutations. The potential impact of such a breakthrough would be nothing short of revolutionary.
Epigenetic Frontiers with Tune Therapeutics: Among Yosemite’s portfolio companies, Tune Therapeutics stands out as a premier epigenetic editing firm in clinical development. Epigenetic editing involves adding or removing "methyl groups"—small chemical tags that attach to DNA and act like a dimmer switch, turning a gene’s activity up or down without altering the underlying DNA sequence. This technology holds immense promise for conditions like hepatitis B, which affects over 250 million people globally and is a primary driver of liver cancer. Tune aims to methylate and silence the hepatitis B virus itself, mimicking the natural process observed in the approximately 1% of individuals who spontaneously clear the virus. This approach has broader implications, as epigenetic changes are also linked to an aging immune system and slowing metabolism, suggesting potential applications beyond infectious diseases.
Histosonics and Novel Device Therapies: An unusual but strategic investment for Yosemite is Histosonics, a device company. While Yosemite primarily focuses on therapeutics, Histosonics represents a cutting-edge approach to tumor destruction. The company is pioneering the use of histotripsy at scale for liver tumor ablation. This non-invasive therapy utilizes focused ultrasound waves to create microscopic air pockets within targeted tissue. These pockets are then collapsed in a controlled manner, precisely destroying cancerous cells without damaging surrounding healthy tissue, akin to a highly focused ultrasound rather than a conventional CT scan. With lead programs in pancreatic and liver tumors—a natural pairing given that most pancreatic cancers metastasize to the liver—Histosonics aims to become a significant part of future cancer treatment protocols.
Other notable portfolio companies include Azalea, which emerged from a grant to Nobel laureate Jennifer Doudna’s lab and is now in clinical trials, and Quarry, a company built with serial founder Craig Crews, focused on a novel therapeutic approach called induced proximity. This innovative method involves a drug physically dragging a disease-causing protein next to the cell’s own breakdown system, rather than attempting to block it directly, offering a new paradigm for therapeutic intervention.
Advocacy and Ecosystem: Shaping the Future of Biomedical Research
Beyond its direct investments, Reed Jobs is a vocal advocate for policies that foster biomedical innovation, particularly regarding federal funding for research. Last year, he publicly voiced concerns over proposed cuts to the National Institutes of Health (NIH) budget. While the immediate threat has somewhat subsided, pressure from the federal government persists. Jobs recounted that an administration previously sought a staggering 40% cut to the NIH budget—an unprecedented proposal, especially when contrasted with the largest historical cut of 1% in 2009, which resulted in 7,000 NIH scientists losing their jobs. Gratefully, both the Senate and House, in a rare display of bipartisanship, overwhelmingly rejected the 40% cut. This year, a 12% cut was proposed, which Jobs also expects to be rejected, given that NIH funding consistently enjoys over 90% public approval. Personally, Jobs argues for an offensive strategy, advocating for an increase to approximately $100 billion, noting that NIH funding has stagnated on a dollar basis for about a decade, effectively shrinking relative to inflation. Robust NIH funding is crucial as it underpins the foundational academic research that eventually feeds into the biotech ecosystem Yosemite operates within.
Yosemite’s commitment to fostering innovation extends to its interactions with founders. The firm maintains an "open door" policy, emphasizing a meritocratic evaluation process. When assessing grants and companies, Jobs states that CVs are deliberately removed from the initial review, ensuring that ideas are judged on their scientific merit alone, irrespective of the applicant’s prior accolades or institutional affiliation. This approach allows them to fund both Nobel laureate labs and first-time grant recipients, evaluating every modality from small molecules to gene therapy, immunotherapy, AI, and digital health. Jobs actively encourages founders with any idea that can impact cancer patients to reach out.
In the realm of biotech entrepreneurship, Jobs acknowledges that "storytelling" is, unfortunately, as critical as in other industries. He has witnessed promising science falter due to poor communication from a CEO. However, he notes that in biotech, the founder (often an academic, chief scientist, or chief medical officer) and the CEO (a professional operator focused on capital raising and external communication) are typically distinct roles, a division of labor that often proves highly effective. He also advises founders to view pharmaceutical partnerships as a "moving target," emphasizing the need to stay attuned to shifting priorities within large pharma, as demonstrated by companies like Pfizer exiting infectious disease after COVID-19.
The Unexpected Catalyst: GLP-1s and a Renewed Ambition
Reflecting on his three years at the helm of Yosemite, Reed Jobs identifies the emergence of GLP-1 agonists (such as Ozempic and Wegovy) as the biggest surprise and a profound catalyst for the broader biomedical landscape. These drugs, primarily known for their efficacy in weight loss and diabetes management, have propelled Eli Lilly to become the first trillion-dollar pharmaceutical company, making GLP-1s the best-selling drug class globally.
Beyond their immediate impact on metabolic health, GLP-1s are showing early signs of being protective against neurodegenerative diseases and even cancer, independently of weight loss. Jobs highlights that obesity, much like smoking, is one of only two "pan-disease" risk factors that significantly elevate the risk across nearly every disease category. This revelation has injected "fresh eyes, fresh ambition, and real capital" into vast disease areas that had previously been overlooked or considered too challenging.
This renewed vigor has brought historically "undruggable" oncogenes like KRAS, Myc, beta-catenin, and p53—the "pantheon of oncogenes" that have evaded therapeutic intervention for decades—within perceived reach. Jobs admits that he did not anticipate Yosemite moving with such velocity. This accelerated pace, fueled by both scientific breakthroughs and a revitalized investment climate, has made the current moment feel both "scarier and more empowering."
A Pragmatic View on Longevity
While personally invested in the concept of longevity and expressing a desire to avoid premature death, Reed Jobs holds a pragmatic and scientifically grounded perspective on the burgeoning longevity industry. He believes that the scientific community, as a whole, is still in the early stages of truly understanding aging.
Jobs points out the absence of a "grand unified theory of aging," akin to the foundational principles in physics. Instead, different scientific disciplines offer disparate explanations: geneticists might emphasize telomeres, immunologists might focus on the declining efficacy of T cells, and metabolomicists would propose entirely different mechanisms. He posits that aging is not a singular "problem" but rather a complex interaction of different cell types aging uniquely across the body. While optimizing individual health outcomes through personalized healthcare is a crucial endeavor, Jobs questions the viability of turning "longevity" into a one-size-fits-all business model, underscoring the profound complexity of reversing or significantly extending the human lifespan.
In conclusion, Reed Jobs’ Yosemite Ventures stands as a dynamic and increasingly influential force in oncology. Through its innovative hybrid funding model, aggressive pursuit of undruggable targets, strategic integration of AI, and advocacy for a robust research ecosystem, the firm is not just investing in the future of cancer treatment but actively shaping it. The confluence of scientific breakthroughs, market shifts, and technological advancements like AI has created an unparalleled moment for progress, positioning Yosemite at the forefront of the global fight against cancer.
